JPH06506671A - Novel thalidomide derivative, method for producing the same, and method for using the same as a drug - Google Patents
Novel thalidomide derivative, method for producing the same, and method for using the same as a drugInfo
- Publication number
- JPH06506671A JPH06506671A JP4507147A JP50714792A JPH06506671A JP H06506671 A JPH06506671 A JP H06506671A JP 4507147 A JP4507147 A JP 4507147A JP 50714792 A JP50714792 A JP 50714792A JP H06506671 A JPH06506671 A JP H06506671A
- Authority
- JP
- Japan
- Prior art keywords
- ch2ch2
- thalidomide
- general formula
- formula
- racemic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical class O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 title claims description 30
- 239000003814 drug Substances 0.000 title claims description 13
- 229940079593 drug Drugs 0.000 title claims description 10
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 238000000034 method Methods 0.000 title claims description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- -1 4-chloromethylbenzoin Chemical compound 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000012876 carrier material Substances 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 210000000987 immune system Anatomy 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
- 238000010276 construction Methods 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 230000003287 optical effect Effects 0.000 claims 1
- 229960003433 thalidomide Drugs 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 2
- 239000008098 formaldehyde solution Substances 0.000 description 2
- 230000006057 immunotolerant effect Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YTEUDCIEJDRJTM-UHFFFAOYSA-N 2-(chloromethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCl YTEUDCIEJDRJTM-UHFFFAOYSA-N 0.000 description 1
- LZHQPJSJEITGHB-UHFFFAOYSA-N 2-[1-(hydroxymethyl)-2,6-dioxopiperidin-3-yl]isoindole-1,3-dione Chemical compound O=C1N(CO)C(=O)CCC1N1C(=O)C2=CC=CC=C2C1=O LZHQPJSJEITGHB-UHFFFAOYSA-N 0.000 description 1
- OITNBJHJJGMFBN-UHFFFAOYSA-N 4-(chloromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CCl)C=C1 OITNBJHJJGMFBN-UHFFFAOYSA-N 0.000 description 1
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 206010024229 Leprosy Diseases 0.000 description 1
- 206010054107 Nodule Diseases 0.000 description 1
- 206010037083 Prurigo Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- HKMQIMRNLKRFFU-UHFFFAOYSA-N [N].O=C1CCCC(=O)N1 Chemical compound [N].O=C1CCCC(=O)N1 HKMQIMRNLKRFFU-UHFFFAOYSA-N 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000004020 conductor Substances 0.000 description 1
- WUESWDIHTKHGQA-UHFFFAOYSA-N cyclohexylurea Chemical compound NC(=O)NC1CCCCC1 WUESWDIHTKHGQA-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Virology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 新規サリドマイド誘導体、その製造方法並びにこれを薬剤として使用する方法本 発明は、一般式■ の新規サリドマイド誘導体、この化合物を含有する薬剤並びにこの化合物及び薬 剤の製造方法に関する。[Detailed description of the invention] New thalidomide derivative, its production method, and method for using it as a drug. The invention is based on the general formula ■ new thalidomide derivatives, drugs containing this compound and this compound and drugs The present invention relates to a method for producing a drug.
サリドマイド（３−フタルイミドービペリジン−２，６−シオン）が免疫抑制的 かつ免疫耐性的に作用することは知られている。しかしこの化合物の治療適用に 関して、その僅かな水溶性が大きな欠点であり、その結果としてサリドマイドは 従来経口投与しかできず、それによって胃腸域中で大きい粘膜欠損と同時に現れ る疾患、たとえば移植一対−ホスト疾患で吸収障害が生じ、そしてそれと結びつ いて血しょう濃度の著しい変動が生じる。Thalidomide (3-phthalimidobiperidine-2,6-sion) is immunosuppressive It is also known to act in an immunotolerant manner. However, therapeutic applications of this compound As for thalidomide, its slight water solubility is a major drawback; Traditionally, only oral administration is possible, which results in the simultaneous appearance of large mucosal defects in the gastrointestinal region. Absorptive disorders occur and are associated with diseases such as transplant-to-host disease. significant fluctuations in plasma concentrations occur.
したがって本発明が基礎とする課題は、サリドマイドと少なくとも同等の免疫抑 制及び免疫耐性作用を有し、かつ特に腸管外投与に適する水溶性サリドマイド誘 導体を発展させることにある。Therefore, the problem on which the present invention is based is to obtain immunosuppressants that are at least as effective as thalidomide. A water-soluble thalidomide inducer with suppressive and immunotolerant effects and particularly suitable for parenteral administration. It is about developing conductors.
本発明者は、新規サリドマイド誘導体がこれに与えられた要求を満足させること を見い出した。The inventors have discovered that new thalidomide derivatives satisfy the requirements set forth herein. I found out.
したがって本発明の対象は、ラセミ又は光学的に活性な形で、一般式■式中基Ｒ １及びＲｔは同−又は異なり、夫々Ｃ＋−ｓ−アルキル基又はＲ１とＲ２が一緒 にナッテ−ＣＨｔＣＨｔ−Ｘ−ＣＨｔＣＨ１−を示し、ｌ？”ｌ：ｔＨ又１．ｔ ｃ）Ｉｓを、Ｘ ハ０ 又ハＮＨテある、なるサリドマイド誘導体及び（又は） その塩である。The subject of the invention is therefore a group R in the general formula (I) in racemic or optically active form. 1 and Rt are the same or different, and each is a C+-s-alkyl group or R1 and R2 are the same shows Natte-CHtCHt-X-CHtCH1-, and l? ”l:tHalso1.t c) A thalidomide derivative and/or where Is is It is the salt.
式中基Ｒ１がＨを意味するサリドマイド誘導体が好ましい。式中基Ｒ１とＰは一 緒になって−Ｃ４ＣＨｔＯＣＨ＊ＣＨｔ−又は−Ｃ）１．Ｃ）１．Ｎ）ＩＣＨ， ＣＨ，−、特に−ＣＨｚＣＨｔＯＣＨ＊Ｃ）Ｉ２−を意味するサリドマイド誘導 体が特に好ましい。Thalidomide derivatives in which the radical R1 in the formula represents H are preferred. In the formula, the groups R1 and P are one Together with -C4CHtOCH*CHt- or -C)1. C)1. N) ICH, Thalidomide induction meaning CH,-, especially -CHzCHtOCH*C)I2- Particularly preferred is the body.
本発明による化合物は、水溶性であり、水性に溶解された又は分散された形で安 定であるので、これは特にヒトの腸管外適用に適する。The compounds according to the invention are water-soluble and stable in aqueous dissolved or dispersed form. This makes it particularly suitable for parenteral application in humans.
したがってもう１つの本発明の対象は、薬剤であり、これは有効物質として少な くとも１個のサリドマイド誘導体及び／又は少なくとも１個の対応する塩をラセ ミ又は光学的に活性な形で有する。Another subject of the invention is therefore drugs, which have little active substance. At least one thalidomide derivative and/or at least one corresponding salt In optically active form.
特に腸管外適用に適する薬学的調製物形、たとえば溶液、懸濁液、容易に再構成 しうる乾燥調製物、軟膏、ペースト、ゲル、溶解された形でデボ−剤中の有効物 質又はプラスターは公知であり、本発明による化合物のこの調製物形への混入は 、当業者にとって問題とならない。この薬剤の本発明による製造で、当然のこと なから担体材料、助剤−及び添加物質、たとえば溶剤、希釈剤、安定剤、分散剤 、湿潤剤、結合剤、染料及び芳香物質の選択を慎重に行わねばならない。特に安 定性及び一本発明による薬剤が液状形で存在する限り一等張圧に注意を払わねば ならない。Pharmaceutical preparation forms particularly suitable for parenteral application, e.g. solutions, suspensions, easily reconstituted The active substance in dry preparations, ointments, pastes, gels, depots in dissolved form. The incorporation of compounds according to the invention into this preparation form is known , does not pose a problem for those skilled in the art. With the production of this drug according to the invention, it is natural that carrier materials, auxiliaries and additive substances such as solvents, diluents, stabilizers, dispersants, etc. , wetting agents, binders, dyes and fragrances must be carefully selected. Especially cheap Attention must be paid to the isotonic pressure as long as the agent according to the invention is present in liquid form. No.
免疫系の疾患、たとえばらい病、ベセト（Ｂｅｃｅｔ）症候群、エリテスト−デ ス、痒疹、結節症、エイズ−疾患に於ける口腔アフタ、潰瘍性大腸炎の処置のた めに及び特に移植一対−ホスト疾患の処置のために、本発明による薬剤は、静脈 内、皮膚内、筋肉内及び鼻腔内並びに局所的に、たとえば皮膚、粘膜及び眼の感 染に適用することができる。Diseases of the immune system, such as leprosy, Becet syndrome, and erectile dysfunction. For the treatment of oral aphthous, ulcerative colitis, prurigo, nodules, AIDS-diseases. and in particular for the treatment of transplant-to-host diseases, the medicament according to the invention can be administered intravenously. internally, intracutaneously, intramuscularly and intranasally, and locally, e.g. on the skin, mucous membranes and eyes. Can be applied to dyeing.
もう一つの本発明の対象は、ラセミ又は光学的に活性な形で、一般式Ｉ式中基Ｒ １及びＲ２は同−又は異なり、夫々Ｃ＋ギアルキル基又はＲ１とＲ８は一緒にな って−ＣＨ，ＣＩ（！−Ｘ−ＣＨ，ＣＩ（１−を示し、Ｒ３はＨ又１；ｔＣ）ｌ ｓを、ｘはｏ又１＊ＮＨテある、なるサリドマイド誘導性及び（又は）その塩を 製造するにあたり、ラセミ又は光学的に活性な形で一般式■ なる化合物とホルムアルデヒドとを反応させて一般式■なるＮ−ヒドロキシメチ ル化合物となし、得られたＮ−ヒドロキシメチル化合物を４−クロルメチル安息 香酸でジシクロへキシルカルボジイミドの存在下に一般式■なるエステルに変え 、これからジ＜Ｃ＋−＊−アルキル）アミン、モルホリン又はピペラジンと反応 させて一般式Ｉのサリドマイド誘導体を製造し、これから場合により酸を用いて 対応する塩が得られることを特徴とする、上記一般式Ｉの化合物の製造方法であ る。Another subject of the invention is the radical R in the general formula I, in racemic or optically active form. 1 and R2 are the same or different, each C+ gearkyl group, or R1 and R8 together -CH,CI(!-X-CH,CI(1-, R3 is H or 1; tC)l s, x is o or 1*NHte, and/or thalidomide derivatives and/or salts thereof In production, in racemic or optically active form, the general formula ■ By reacting a compound with formaldehyde, N-hydroxymethylene of the general formula The resulting N-hydroxymethyl compound was added to 4-chloromethylbenzene. In the presence of dicyclohexylcarbodiimide with aromatic acid, it is converted to an ester with the general formula ■ , which is then reacted with di<C+-*-alkyl)amine, morpholine or piperazine. to prepare a thalidomide derivative of general formula I, which is then optionally treated with an acid. A process for producing a compound of general formula I above, characterized in that the corresponding salt is obtained. Ru.
本発明によるサリドマイド誘導体の製造用出発化合物として、グルタルイミド窒 素原子がホルムアルデヒドによって公知方法でヒドロキシルメチル化されている サリドマイドを使用するのが好ましい。溶剤又は溶剤混合物中でジシクロへキシ ルカルボジイミドの存在下に４−クロルメチル安息香酸と反応させた後、好まし くはモルホリン又はピペラジン、特に好ましくはモルホリンをアルカリハロゲニ ト、たとえばヨウ化ナトリウムの存在下に水不含溶剤又は溶剤混合物中で反応さ せることによって、本発明によるサリドマイド誘導体が得られ、次いでこれを所 望の場合には酸、たとえば塩酸で、場合によりＣ３−３−アルキルアルコールの 存在下に対応する塩に変える。Glutarimide nitrogen is used as a starting compound for the production of thalidomide derivatives according to the invention. The elementary atom is hydroxylmethylated by formaldehyde in a known manner. Preferably, thalidomide is used. Dicyclohexy in solvent or solvent mixture After reaction with 4-chloromethylbenzoic acid in the presence of carbodiimide, preferably or morpholine or piperazine, particularly preferably morpholine with an alkali halide. reaction in a water-free solvent or solvent mixture, for example in the presence of sodium iodide. The thalidomide derivative according to the invention is obtained by If desired, an acid, for example hydrochloric acid, optionally a C3-3-alkyl alcohol. in the presence of the corresponding salt.
例 Ｎ−（４−モルホリノメチル−ベンゾイルオキシメチル）−サリドマイド、ヒド ロクロリド塩の製造 サリドマイド２．５８ｇを、３５重量％ホルムアルデヒド−溶液３０ｍ１中で澄 明溶液が形成するまで還流下に加熱し、次いて２０°Ｃに冷却する。２４時間後 、濾過し、残留物を３重量％ホルムアルデヒド溶液で洗滌し、乾燥する。融点１ ６５°ＣのＮ−ヒドロキシメチルーサリドマイドが７０％収率で得られる。example N-(4-morpholinomethyl-benzoyloxymethyl)-thalidomide, hydro Manufacture of lochloride salt 2.58 g of thalidomide was clarified in 30 ml of a 35% by weight formaldehyde solution. Heat under reflux until a bright solution forms, then cool to 20°C. 24 hours later , filter, wash the residue with 3% by weight formaldehyde solution and dry. Melting point 1 N-hydroxymethyl-thalidomide at 65°C is obtained with a yield of 70%.
ジクロルメタン２５ｍ１中のＮ−ヒドロキシメチルーサリドマイ自、１ｇ、４− クロルメチル安息香酸０．６８ｇ、ジシクロへキシルカルボジイミド王０３ｇ及 び４−ピロリジノピリジン０．０６ｇを２４時間、２０°Ｃで撹拌する。次いで シクロヘキシル尿素を濾去し、ジクロルメタンを蒸留で除去する。得られた残留 物を、エタノール中で再結晶する。融点２＋５−２２０℃のＮ−（４−クロルメ チルーペンゾイルオキシメチノいサリドマイドが、６０％収率で得られる。1 g of N-hydroxymethyl-thalidomycin in 25 ml of dichloromethane, 4- 0.68g of chloromethylbenzoic acid, 03g of dicyclohexylcarbodiimide and and 0.06 g of 4-pyrrolidinopyridine were stirred at 20°C for 24 hours. then The cyclohexylurea is filtered off and the dichloromethane is removed by distillation. Residual obtained The product is recrystallized in ethanol. N-(4-chlormethane) with melting point 2+5-220℃ Thilupenzoyloxymethino thalidomide is obtained with a yield of 60%.
Ｎ−（４−クロルメチル−ベンゾイルオキシメチル）サリドマイド８８０ｍｇ 、モルホリン３５０ｍｇ及びヨウ化ナトリウム２０ｍｇを、無水アセトン中で２ ４時間、２０°Ｃて撹拌する。次いでアセトンを蒸留で除去し、油状残留物をカ ラムクロマトグラフィーによりシリカゲル６０（溶離剤：酢酸エチル）で精製す る。得られた油状物を、エタノール性塩酸中に溶解し、ジエチルエーテルの添加 後沈殿する。エタノール中で再結晶後、融点２３６°ＣのＮ−（４−モルホリノ メチル−ベンゾイルオキシメチル）サリドマイド、ヒドロクロリドが４０％収率 で得られる。N-(4-chloromethyl-benzoyloxymethyl)thalidomide 880mg , 350 mg of morpholine and 20 mg of sodium iodide in anhydrous acetone. Stir for 4 hours at 20°C. The acetone is then removed by distillation and the oily residue is evaporated. Purified by ram chromatography on silica gel 60 (eluent: ethyl acetate). Ru. The resulting oil was dissolved in ethanolic hydrochloric acid and added with diethyl ether. Precipitates later. After recrystallization in ethanol, N-(4-morpholino 40% yield of methyl-benzoyloxymethyl) thalidomide, hydrochloride It can be obtained with
’Ｈ−ＮＭＲ（２００ＭＨｚ、 ＤＭＳＯ−ｄｇ） ： ２．０８．２．６２（ ｍ、 ｍ、 ２Ｈ，ＣＨｚ−ＣＨ）；２．８４．２．９１（ｍ、 ｍ、 ２Ｈ， ＣＨｔＣＯ）；３、１０．３．７０（ｍ、 ｍ、 ８Ｈ，−ＣＨｔ−ＣＨＪ ； ４．４１（ｓ、 ２Ｈ，−ＣＨ，−Ｎ＞：５．３５．５．４３（ｄｄ、 １）１ ． ＣＨ−ＣＨ，）：５．９２（ｄ、 ２Ｈ，Ｎ−ＣＨｔ−０）ニア、７２．７ ．９２（ｍ、 ｔｎ、 ８Ｎ、芳香族）；１１．２０（ｓ、 １）１． Ｈ）'H-NMR (200MHz, DMSO-dg): 2.08.2.62 ( m, m, 2H, CHz-CH); 2.84.2.91 (m, m, 2H, CHtCO); 3, 10.3.70 (m, m, 8H, -CHt-CHJ; 4.41(s, 2H, -CH, -N>:5.35.5.43(dd, 1)1 ．． CH-CH,): 5.92 (d, 2H, N-CHt-0) near, 72.7 ．． 92 (m, tn, 8N, aromatic); 11.20 (s, 1) 1. H)
Claims (10)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4112566.5 | 1991-04-17 | ||
| DE4112566 | 1991-04-17 | ||
| PCT/EP1992/000790 WO1992018496A1 (en) | 1991-04-17 | 1992-04-08 | New thalidomide derivatives, method of manufacture and use thereof in medicaments |
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| Publication Number | Publication Date |
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| JPH06506671A true JPH06506671A (en) | 1994-07-28 |
| JP3204972B2 JP3204972B2 (en) | 2001-09-04 |
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| JP50714792A Expired - Fee Related JP3204972B2 (en) | 1991-04-17 | 1992-04-08 | Novel thalidomide derivative, method for producing the same, and method of using the same as drug |
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| EP (1) | EP0580641B1 (en) |
| JP (1) | JP3204972B2 (en) |
| AT (1) | ATE146787T1 (en) |
| AU (1) | AU661299B2 (en) |
| CA (1) | CA2104776C (en) |
| DE (2) | DE59207778D1 (en) |
| DK (1) | DK0580641T3 (en) |
| ES (1) | ES2098505T3 (en) |
| GR (1) | GR3022175T3 (en) |
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| US6114355A (en) * | 1993-03-01 | 2000-09-05 | D'amato; Robert | Methods and compositions for inhibition of angiogenesis |
| US8143283B1 (en) | 1993-03-01 | 2012-03-27 | The Children's Medical Center Corporation | Methods for treating blood-born tumors with thalidomide |
| US5629327A (en) | 1993-03-01 | 1997-05-13 | Childrens Hospital Medical Center Corp. | Methods and compositions for inhibition of angiogenesis |
| DE19613976C1 (en) * | 1996-04-09 | 1997-11-20 | Gruenenthal Gmbh | Thalidomide prodrugs with immunomodulatory effects |
| CA2256669A1 (en) * | 1996-05-29 | 1997-12-04 | Prototek, Inc. | Prodrugs of thalidomide and methods for using same as modulators of t-cell function |
| HU228769B1 (en) * | 1996-07-24 | 2013-05-28 | Celgene Corp | Substituted 2(2,6-dioxopiperidin-3-yl)phthalimides and -1-oxoisoindolines and their use for production of pharmaceutical compositions for mammals to reduce the level of tnf-alpha |
| JP2002513391A (en) | 1996-11-05 | 2002-05-08 | ザ チルドレンズ メディカル センター コーポレイション | Methods and compositions for inhibiting angiogenesis |
| DE19703763C1 (en) * | 1997-02-01 | 1998-10-01 | Gruenenthal Gmbh | Thalidomide-analogous compounds from the class of the piperidine-2,6-diones |
| DE19743968C2 (en) * | 1997-10-06 | 2002-07-11 | Gruenenthal Gmbh | Intravenous application form of thalidomide for the therapy of immunological diseases |
| EP1064277B1 (en) | 1998-03-16 | 2005-06-15 | Celgene Corporation | 2-(2,6-dioxopiperidin-3-yl)isoindoline derivatives, their preparation and their use as inhibitors of inflammatory cytokines |
| US6673828B1 (en) | 1998-05-11 | 2004-01-06 | Children's Medical Center Corporation | Analogs of 2-Phthalimidinoglutaric acid |
| ATE235256T1 (en) | 1999-03-31 | 2003-04-15 | Gruenenthal Gmbh | STABLE AQUEOUS SOLUTION OF 3-(1-OXO-1,3-DIHYDRO-ISOINDOL-2-YL)-PIPERIDINE-2,6-DIONE |
| US7091353B2 (en) | 2000-12-27 | 2006-08-15 | Celgene Corporation | Isoindole-imide compounds, compositions, and uses thereof |
| US7320991B2 (en) | 2001-02-27 | 2008-01-22 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health | Analogs of thalidomide as potential angiogenesis inhibitors |
| CN100488959C (en) * | 2003-03-27 | 2009-05-20 | 天津和美生物技术有限公司 | Water soluble thalidomide derivative |
| CA2808646C (en) | 2003-09-17 | 2016-08-23 | The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services | Thalidomide analogs as tnf-alpha modulators |
| US8952895B2 (en) | 2011-06-03 | 2015-02-10 | Apple Inc. | Motion-based device operations |
| US20110104186A1 (en) | 2004-06-24 | 2011-05-05 | Nicholas Valiante | Small molecule immunopotentiators and assays for their detection |
| US8927725B2 (en) | 2011-12-02 | 2015-01-06 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Thio compounds |
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| GB768821A (en) * | 1954-05-17 | 1957-02-20 | Gruenenthal Chemie | Novel products of the amino-piperidine-2, 6-dione series |
| DE1670391A1 (en) * | 1965-05-08 | 1970-11-05 | Gruenenthal Chemie | Dicarboximide derivatives and processes for their preparation |
| DE1545706A1 (en) * | 1965-05-08 | 1969-10-09 | Gruenenthal Chemie | Dicarboximide derivatives and processes for their preparation |
| DE1545672B2 (en) * | 1965-05-08 | 1974-11-07 | Chemie Gruenenthal Gmbh, 5190 Stolberg | Dicarboximide derivatives and processes for their preparation |
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| JP2014224119A (en) * | 2008-10-29 | 2014-12-04 | セルジーン コーポレイション | Isoindoline compounds for use in cancer treatment |
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| DE4211812C2 (en) | 1994-05-05 |
| DE59207778D1 (en) | 1997-02-06 |
| GR3022175T3 (en) | 1997-03-31 |
| EP0580641B1 (en) | 1996-12-27 |
| AU1455592A (en) | 1992-11-17 |
| EP0580641A1 (en) | 1994-02-02 |
| JP3204972B2 (en) | 2001-09-04 |
| CA2104776A1 (en) | 1992-10-18 |
| DE4211812A1 (en) | 1992-10-22 |
| ATE146787T1 (en) | 1997-01-15 |
| AU661299B2 (en) | 1995-07-20 |
| HK1005188A1 (en) | 1998-12-24 |
| DK0580641T3 (en) | 1997-01-20 |
| CA2104776C (en) | 2003-12-09 |
| WO1992018496A1 (en) | 1992-10-29 |
| ES2098505T3 (en) | 1997-05-01 |
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